RARE DISEASE
Therapy related acute myeloid leukemia and myelodysplastic syndrome
Therapy related acute myeloid leukemia and myelodysplastic syndrome
Therapy related acute myeloid leukemia and myelodysplastic syndrome
Synonyms: Secondary AML, Secondary acute myeloid leukemia, Therapy-related AML and myelodysplastic syndrome
Synonyms: Secondary AML, Secondary acute myeloid leukemia, Therapy-related AML and myelodysplastic syndrome
Synonyms: Secondary AML, Secondary acute myeloid leukemia, Therapy-related AML and myelodysplastic syndrome
Drug discovery
0
drugs
With orphan designations
Overview
Therapy-related acute myeloid leukemia and myelodysplastic syndromes (t-AML/MDS) are aggressive clonal disorders arising after cytotoxic chemotherapy and/or radiotherapy. Characterized by high-risk genetic abnormalities and poor prognoses, they typically manifest 3–5 years post-treatment, with shorter latency after hematopoietic cell transplantation (HCT) [1][8]. Two distinct subtypes exist: alkylating agent/radiation-associated cases often show TP53 mutations and chromosome 5/7 abnormalities, while topoisomerase II inhibitor-linked cases frequently involve KMT2A rearrangements [1][8][9]. Median survival remains <1 year without allogeneic HCT [1][4].
Population
Primarily affects cancer survivors treated with chemoradiotherapy (e.g., Hodgkin/non-Hodgkin lymphoma, breast cancer) [1][2][9]
Risk elevated by alkylators, radiation, and HCT conditioning regimens [2][8]
10-20% of adult AML/MDS cases; incidence rising with expanded use of DNA-damaging therapies [5][8]
Therapies
Allogeneic HCT remains cornerstone for eligible patients, offering 30-43% long-term survival [1][4][8]
Hypomethylating agents (azacitidine/decitabine) as bridge to transplant or palliative option [6][9]
Supportive care with transfusions, growth factors, and infection prophylaxis for non-HCT candidates [3][9]
Categories: rare hematological diseases, rare neoplastic diseases, rare transplant-related disorders
Research Papers
3,254 drug discovery papers about Therapy related acute myeloid leukemia and myelodysplastic syndrome, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
3,254 drug discovery papers about Therapy related acute myeloid leukemia and myelodysplastic syndrome, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-17 | Real-world outcomes of venetoclax plus hypomethylating agents in unfit acute myeloid leukaemia: Results of the GIMEMA AML2320 trial.
Venetoclax (VEN) plus hypomethylating agents (HMAs) represents the standard of care for newly diagnosed acute myeloid leukaemia (AML) patients unfit for intensive chemotherapy, but prospective real-world observational data outside randomized clinical trials remain limited. The Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) AML2320 is a prospective, multicentre, observational study (NCT04589728) including 193 newly diagnosed unfit AML patients receiving VEN plus azacitidine or decitabine between November 2020 and December 2021. Primary end-point was overall survival (OS); secondary end-points included composite complete remission (cCR), disease-free survival and safety. Median age was 74 years with 42% of patients being ≥75 years. After completing cycle 4, cCR was achieved in 73% of the patients, with 54% responding before cycle 2. After a median follow-up of 23 months, median OS was 13.0 months. cCR achievement within cycle 4 correlated with longer OS (19.1 vs. 9.1 months, p = 0.001). Patients receiving 400 mg VEN without azoles had improved OS compared with those on reduced doses with azoles (18.2 vs. 11.4 months, p = 0.015). An anchored matching-adjusted indirect comparison with the phase III VIALE-A trial (NCT02993523) showed comparable median OS (14.8 months vs. 14.9 months; p = 0.6). The GIMEMA AML2320 trial confirmed the efficacy of VEN/HMAs in a prospective, real-world unfit population. Early remission was associated with improved outcomes.
2026-08-15 | Epigenetic Priming with Azacitidine Prior to Allogeneic Hematopoietic Stem Cell Transplantation for Myeloid Malignancies.
Relapse remains the leading cause of treatment failure following allogeneic hematopoietic stem cell transplantation (alloHCT) for high-risk myeloid malignancies. Epigenetic dysregulation contributes to leukemogenesis and therapeutic resistance. OBJECTIVE: : To investigate whether pre-transplant epigenetic priming with azacitidine enhances chemosensitivity and improves alloHCT outcomes. We conducted an open-label, prospective phase II study evaluating azacitidine incorporated into reduced-intensity conditioning in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) undergoing alloHCT from matched related or unrelated donors. The primary endpoints were overall survival (OS) and progression-free survival (PFS). Secondary endpoints included relapse incidence, non-relapse mortality (NRM), and pharmacodynamic evaluation of DNA methylation changes in bone marrow CD34+ cells. Thirty-nine patients were enrolled. Most patients had AML (85%), 62% with adverse-risk AML or high/very high-risk MDS, and 23% had TP53 mutations. Neutrophil and platelet engraftment occurred in 97% of patients at median of 13 and 16 days, respectively. One-year OS and PFS were 64% and 54%, respectively, with NRM of 15% and relapse incidence of 31%. Pharmacodynamic analyses demonstrated azacitidine-induced DNA hypomethylation in bone marrow CD34+ cells, which correlated with improved survival. Higher baseline methylation levels were also associated with superior survival. Azacitidine priming prior to alloHCT is feasible and demonstrates encouraging survival outcomes in high-risk myeloid malignancies. Epigenetic priming induces measurable biologic reduction of DNA methylation that is plausibly linked to improved relapse-free survival. These findings support further evaluation in randomized studies and suggest DNA methylation may serve as a predictive biomarker of response.
2026-08-12 | Treatment Modalities and the Impact of Granulocyte Colony-Stimulating Factor in AML Patients Treated With Venetoclax and Azacitidine: A DATAML Registry Study.
Azacitidine-venetoclax (AZA-VEN) has become a standard treatment in older or chemotherapy-ineligible AML patients. While the registration trial showed a median overall survival (OS) of 14.7 months, most real-world studies have not reproduced this result. We analyzed treatment patterns, adverse events, responses and outcomes in 199 patients treated with AZA-VEN in the DATAML registry. The median age was 75.6 years, 48.7% had secondary AML (11% post-MPN); 11.7% had another cancer, and 9% had received AZA for prior myelodysplastic syndrome. Cytogenetic risk was intermediate (55.8%) or adverse (43.7%). The most frequent gene mutations were ASXL1 (33%), TET2 (27%), TP53 (26%), RUNX1 (24%) and SRSF2 (24%). The first cycle was performed on an outpatient basis in 39.4% of patients. The median number of cycles was 4 and 37% received > 6 cycles. Beyond cycle 6, reductions in treatment dose or duration were attributed to VEN in 55% of patients and to AZA for 43%. The complete remission (CR) plus CR with incomplete hematologic recovery (CRi) rate was 58.5%, and day-30 death rate was 3%. Median OS was 8.9 months. mPRS and refined-ELN2024 classifications were significantly associated with response and OS. In CR/CRi patients, G-CSF use was significantly and independently associated with improved OS (median, 10.1 months without versus 20.3 with G-CSF; P = .001). In an external cohort, G-CSF was also associated with a trend towards improved OS. In real-world clinical practice, patients with more severe characteristics are typically selected for AZA-VEN, which could explain suboptimal outcomes. G-CSF should be prospectively explored in AZA-VEN treated patients.
2026-08-08 | Prognostic factors for early mortality following allogeneic hematopoietic cell transplantation in hematologic malignancies.
The 100 days following allogeneic hematopoietic stem cell transplantation (allo-HCT) remains a critical period despite advancements in transplant-related care. Post-transplant cyclophosphamide (PTCy) has been implemented as an effective strategy for GVHD prevention across various donor types. This study aimed to evaluate causes of early mortality and prognostic factors for non-relapse mortality (NRM), disease-related mortality (DRM), and overall survival (OS). This was a single institution, retrospective study including adult patients who received their first allo-HCT from 2009 to 2023. Patient- and transplant- related variables were compared between patients who died and those who were alive at 100 days post-allo-HCT. A total of 536 patients were evaluated, including 285 men (53%). Median age at time of allo-HCT was 59 years (range 19-75), and most were White/Caucasian (n=232; 86%). The predominant diagnosis included acute myeloid leukemia (AML) (n=195, 36%), myelodysplastic syndrome (MDS) (n=95, 18%), and myelofibrosis (MF) (n=57, 11%). Eighty patients (15%) died within 100 days following allo-HCT, with NRM accounting for most early deaths (N=61; 76%). Primary causes of death were acute GVHD (n = 23), disease relapse/progression (n = 19), and infections (n = 18). On multivariate analysis, earlier transplant year was the only independent predictor of increased 100-day DRM (HR 1.15; p=0.049). Male gender (HR 1.78; p=0.035), non-acute leukemia diagnoses (HR 2.38; p=0.003), and non-PTCy prophylaxis (HR 2.2; p=0.032) were independently associated with higher 100-day NRM. PTCy-based GVHD prophylaxis was the only modifiable factor associated with lower early NRM, through reduced GVHD-related deaths without increased infection or DRM.
2026-08-06 | Defining a Therapeutic Window for Venetoclax in Post-Transplant Maintenance Therapy for High-Risk Acute Myeloid Leukemia and Myelodysplastic Syndromes.
Patients with high-risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) continue to face a substantial risk of relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT), which remains a leading cause of treatment failure. In our previous study, maintenance therapy with a combination of venetoclax and decitabine has shown potential in reducing relapse rates; however, its efficacy and safety, particularly in relation to drug concentration levels, are not yet fully elucidated. This study aimed to evaluate the influence of venetoclax blood concentrations on the efficacy and toxicity of venetoclax plus decitabine as maintenance therapy in high-risk AML/MDS patients after allo-HSCT. We retrospectively analyzed clinical data from 58 high-risk AML/MDS patients who received this maintenance regimen at our center between April 2018 and June 2023, with a focus on the association between venetoclax blood levels, treatment response, and adverse effects. The results demonstrated that the venetoclax-decitabine maintenance regimen was effective and generally well-tolerated, improving remission rates without significantly increasing intolerable toxicities or the risk of graft-versus-host disease (GVHD). Notably, substantial interindividual variability in venetoclax blood concentrations was observed. Patients with concentrations maintained within the range of 2605-4060 ng/mL achieved superior outcomes and higher safety profiles. In conclusion, this study provides key evidence for establishing a target concentration window for venetoclax, highlighting the importance of therapeutic drug monitoring in guiding post-transplant maintenance therapy for high-risk AML/MDS patients.
2026-08-17 | Real-world outcomes of venetoclax plus hypomethylating agents in unfit acute myeloid leukaemia: Results of the GIMEMA AML2320 trial.
Venetoclax (VEN) plus hypomethylating agents (HMAs) represents the standard of care for newly diagnosed acute myeloid leukaemia (AML) patients unfit for intensive chemotherapy, but prospective real-world observational data outside randomized clinical trials remain limited. The Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) AML2320 is a prospective, multicentre, observational study (NCT04589728) including 193 newly diagnosed unfit AML patients receiving VEN plus azacitidine or decitabine between November 2020 and December 2021. Primary end-point was overall survival (OS); secondary end-points included composite complete remission (cCR), disease-free survival and safety. Median age was 74 years with 42% of patients being ≥75 years. After completing cycle 4, cCR was achieved in 73% of the patients, with 54% responding before cycle 2. After a median follow-up of 23 months, median OS was 13.0 months. cCR achievement within cycle 4 correlated with longer OS (19.1 vs. 9.1 months, p = 0.001). Patients receiving 400 mg VEN without azoles had improved OS compared with those on reduced doses with azoles (18.2 vs. 11.4 months, p = 0.015). An anchored matching-adjusted indirect comparison with the phase III VIALE-A trial (NCT02993523) showed comparable median OS (14.8 months vs. 14.9 months; p = 0.6). The GIMEMA AML2320 trial confirmed the efficacy of VEN/HMAs in a prospective, real-world unfit population. Early remission was associated with improved outcomes.
2026-08-15 | Epigenetic Priming with Azacitidine Prior to Allogeneic Hematopoietic Stem Cell Transplantation for Myeloid Malignancies.
Relapse remains the leading cause of treatment failure following allogeneic hematopoietic stem cell transplantation (alloHCT) for high-risk myeloid malignancies. Epigenetic dysregulation contributes to leukemogenesis and therapeutic resistance. OBJECTIVE: : To investigate whether pre-transplant epigenetic priming with azacitidine enhances chemosensitivity and improves alloHCT outcomes. We conducted an open-label, prospective phase II study evaluating azacitidine incorporated into reduced-intensity conditioning in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) undergoing alloHCT from matched related or unrelated donors. The primary endpoints were overall survival (OS) and progression-free survival (PFS). Secondary endpoints included relapse incidence, non-relapse mortality (NRM), and pharmacodynamic evaluation of DNA methylation changes in bone marrow CD34+ cells. Thirty-nine patients were enrolled. Most patients had AML (85%), 62% with adverse-risk AML or high/very high-risk MDS, and 23% had TP53 mutations. Neutrophil and platelet engraftment occurred in 97% of patients at median of 13 and 16 days, respectively. One-year OS and PFS were 64% and 54%, respectively, with NRM of 15% and relapse incidence of 31%. Pharmacodynamic analyses demonstrated azacitidine-induced DNA hypomethylation in bone marrow CD34+ cells, which correlated with improved survival. Higher baseline methylation levels were also associated with superior survival. Azacitidine priming prior to alloHCT is feasible and demonstrates encouraging survival outcomes in high-risk myeloid malignancies. Epigenetic priming induces measurable biologic reduction of DNA methylation that is plausibly linked to improved relapse-free survival. These findings support further evaluation in randomized studies and suggest DNA methylation may serve as a predictive biomarker of response.
2026-08-12 | Treatment Modalities and the Impact of Granulocyte Colony-Stimulating Factor in AML Patients Treated With Venetoclax and Azacitidine: A DATAML Registry Study.
Azacitidine-venetoclax (AZA-VEN) has become a standard treatment in older or chemotherapy-ineligible AML patients. While the registration trial showed a median overall survival (OS) of 14.7 months, most real-world studies have not reproduced this result. We analyzed treatment patterns, adverse events, responses and outcomes in 199 patients treated with AZA-VEN in the DATAML registry. The median age was 75.6 years, 48.7% had secondary AML (11% post-MPN); 11.7% had another cancer, and 9% had received AZA for prior myelodysplastic syndrome. Cytogenetic risk was intermediate (55.8%) or adverse (43.7%). The most frequent gene mutations were ASXL1 (33%), TET2 (27%), TP53 (26%), RUNX1 (24%) and SRSF2 (24%). The first cycle was performed on an outpatient basis in 39.4% of patients. The median number of cycles was 4 and 37% received > 6 cycles. Beyond cycle 6, reductions in treatment dose or duration were attributed to VEN in 55% of patients and to AZA for 43%. The complete remission (CR) plus CR with incomplete hematologic recovery (CRi) rate was 58.5%, and day-30 death rate was 3%. Median OS was 8.9 months. mPRS and refined-ELN2024 classifications were significantly associated with response and OS. In CR/CRi patients, G-CSF use was significantly and independently associated with improved OS (median, 10.1 months without versus 20.3 with G-CSF; P = .001). In an external cohort, G-CSF was also associated with a trend towards improved OS. In real-world clinical practice, patients with more severe characteristics are typically selected for AZA-VEN, which could explain suboptimal outcomes. G-CSF should be prospectively explored in AZA-VEN treated patients.
2026-08-08 | Prognostic factors for early mortality following allogeneic hematopoietic cell transplantation in hematologic malignancies.
The 100 days following allogeneic hematopoietic stem cell transplantation (allo-HCT) remains a critical period despite advancements in transplant-related care. Post-transplant cyclophosphamide (PTCy) has been implemented as an effective strategy for GVHD prevention across various donor types. This study aimed to evaluate causes of early mortality and prognostic factors for non-relapse mortality (NRM), disease-related mortality (DRM), and overall survival (OS). This was a single institution, retrospective study including adult patients who received their first allo-HCT from 2009 to 2023. Patient- and transplant- related variables were compared between patients who died and those who were alive at 100 days post-allo-HCT. A total of 536 patients were evaluated, including 285 men (53%). Median age at time of allo-HCT was 59 years (range 19-75), and most were White/Caucasian (n=232; 86%). The predominant diagnosis included acute myeloid leukemia (AML) (n=195, 36%), myelodysplastic syndrome (MDS) (n=95, 18%), and myelofibrosis (MF) (n=57, 11%). Eighty patients (15%) died within 100 days following allo-HCT, with NRM accounting for most early deaths (N=61; 76%). Primary causes of death were acute GVHD (n = 23), disease relapse/progression (n = 19), and infections (n = 18). On multivariate analysis, earlier transplant year was the only independent predictor of increased 100-day DRM (HR 1.15; p=0.049). Male gender (HR 1.78; p=0.035), non-acute leukemia diagnoses (HR 2.38; p=0.003), and non-PTCy prophylaxis (HR 2.2; p=0.032) were independently associated with higher 100-day NRM. PTCy-based GVHD prophylaxis was the only modifiable factor associated with lower early NRM, through reduced GVHD-related deaths without increased infection or DRM.
2026-08-06 | Defining a Therapeutic Window for Venetoclax in Post-Transplant Maintenance Therapy for High-Risk Acute Myeloid Leukemia and Myelodysplastic Syndromes.
Patients with high-risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) continue to face a substantial risk of relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT), which remains a leading cause of treatment failure. In our previous study, maintenance therapy with a combination of venetoclax and decitabine has shown potential in reducing relapse rates; however, its efficacy and safety, particularly in relation to drug concentration levels, are not yet fully elucidated. This study aimed to evaluate the influence of venetoclax blood concentrations on the efficacy and toxicity of venetoclax plus decitabine as maintenance therapy in high-risk AML/MDS patients after allo-HSCT. We retrospectively analyzed clinical data from 58 high-risk AML/MDS patients who received this maintenance regimen at our center between April 2018 and June 2023, with a focus on the association between venetoclax blood levels, treatment response, and adverse effects. The results demonstrated that the venetoclax-decitabine maintenance regimen was effective and generally well-tolerated, improving remission rates without significantly increasing intolerable toxicities or the risk of graft-versus-host disease (GVHD). Notably, substantial interindividual variability in venetoclax blood concentrations was observed. Patients with concentrations maintained within the range of 2605-4060 ng/mL achieved superior outcomes and higher safety profiles. In conclusion, this study provides key evidence for establishing a target concentration window for venetoclax, highlighting the importance of therapeutic drug monitoring in guiding post-transplant maintenance therapy for high-risk AML/MDS patients.
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